Combining Oncolytic Virotherapy with p53 Tumor Suppressor Gene Therapy
2017; Elsevier BV; Volume: 5; Linguagem: Inglês
10.1016/j.omto.2017.03.002
ISSN2372-7705
AutoresChristian Bressy, Eric Hastie, Valery Z. Grdzelishvili,
Tópico(s)RNA Interference and Gene Delivery
ResumoOncolytic virus (OV) therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant cells unharmed. With the first U.S. Food and Drug Administration-approved OV, dozens of clinical trials ongoing, and an abundance of translational research in the field, OV therapy is poised to be one of the leading treatments for cancer. A number of recombinant OVs expressing a transgene for p53 (TP53) or another p53 family member (TP63 or TP73) were engineered with the goal of generating more potent OVs that function synergistically with host immunity and/or other therapies to reduce or eliminate tumor burden. Such transgenes have proven effective at improving OV therapies, and basic research has shown mechanisms of p53-mediated enhancement of OV therapy, provided optimized p53 transgenes, explored drug-OV combinational treatments, and challenged canonical roles for p53 in virus-host interactions and tumor suppression. This review summarizes studies combining p53 gene therapy with replication-competent OV therapy, reviews preclinical and clinical studies with replication-deficient gene therapy vectors expressing p53 transgene, examines how wild-type p53 and p53 modifications affect OV replication and anti-tumor effects of OV therapy, and explores future directions for rational design of OV therapy combined with p53 gene therapy. Oncolytic virus (OV) therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant cells unharmed. With the first U.S. Food and Drug Administration-approved OV, dozens of clinical trials ongoing, and an abundance of translational research in the field, OV therapy is poised to be one of the leading treatments for cancer. A number of recombinant OVs expressing a transgene for p53 (TP53) or another p53 family member (TP63 or TP73) were engineered with the goal of generating more potent OVs that function synergistically with host immunity and/or other therapies to reduce or eliminate tumor burden. Such transgenes have proven effective at improving OV therapies, and basic research has shown mechanisms of p53-mediated enhancement of OV therapy, provided optimized p53 transgenes, explored drug-OV combinational treatments, and challenged canonical roles for p53 in virus-host interactions and tumor suppression. This review summarizes studies combining p53 gene therapy with replication-competent OV therapy, reviews preclinical and clinical studies with replication-deficient gene therapy vectors expressing p53 transgene, examines how wild-type p53 and p53 modifications affect OV replication and anti-tumor effects of OV therapy, and explores future directions for rational design of OV therapy combined with p53 gene therapy. Oncolytic virus (OV) therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant ("normal") cells unharmed. The first correlative observations of tumor regression following viral infection were reported in the mid-1800s.1Kelly E. Russell S.J. History of oncolytic viruses: genesis to genetic engineering.Mol. Ther. 2007; 15: 651-659Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar In the last 20 years, the development of new genetic techniques has allowed for an explosion of preclinical and clinical research with almost every major group of animal virus being tested for OV efficacy against most cancer types. There are currently at least three OVs approved for clinical use, including the U.S. Food and Drug Administration-approved2Orloff M. Spotlight on talimogene laherparepvec for the treatment of melanoma lesions in the skin and lymph nodes.Oncolytic Virother. 2016; 5: 91-98Crossref PubMed Google Scholar and The European Commission-approved3Rehman H. Silk A.W. Kane M.P. Kaufman H.L. Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy.J. Immunother. Cancer. 2016; 4: 53Crossref PubMed Scopus (3) Google Scholar talimogene laherparepvec (T-VEC; based on herpes simplex virus 1) for inoperable metastatic melanoma; Riga virus (RIGVIR; based on enteric cytopathic human orphan virus 7) for melanoma in Latvia, Georgia, and Armenia;4Doniņa S. Strēle I. Proboka G. Auziņš J. Alberts P. Jonsson B. Venskus D. Muceniece A. Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study.Melanoma Res. 2015; 25: 421-426Crossref PubMed Scopus (4) Google Scholar and Gendicine and Oncorine (both based on adenovirus type 5) for head and neck squamous cell carcinoma in China.5Garber K. China approves world's first oncolytic virus therapy for cancer treatment.J. Natl. Cancer Inst. 2006; 98: 298-300Crossref PubMed Google Scholar Rational OV development aims to generate ideal OVs that are: (1) highly attenuated in healthy tissues and safe in patients with weakened immune systems (oncoselectivity); (2) highly effective at infecting and killing cancer cells (oncotoxicity); (3) able to stimulate an adaptive immune response against cancer cells; and (4) resistant to premature clearance by the immune system during treatment. Despite encouraging results, OV monotherapy based exclusively on virus replication-induced oncolysis often does not demonstrate all of these desired qualities, especially when tested against virus-resistant malignancies. Today's hurdles facing OV therapies remain the same as those described in early6Chiocca E.A. Guided genes for tumor warfare.Nat. Biotechnol. 2002; 20: 235-236Crossref PubMed Scopus (3) Google Scholar, 7Davis J.J. Fang B. Oncolytic virotherapy for cancer treatment: challenges and solutions.J. 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Here, we focus specifically on OVs engineered to encode a transgene for the tumor protein p53 (TP53). Since its discovery in 197911Kress M. May E. Cassingena R. May P. Simian virus 40-transformed cells express new species of proteins precipitable by anti-simian virus 40 tumor serum.J. Virol. 1979; 31: 472-483PubMed Google Scholar and identification as a tumor suppressor in 1989,12Finlay C.A. Hinds P.W. Levine A.J. The p53 proto-oncogene can act as a suppressor of transformation.Cell. 1989; 57: 1083-1093Abstract Full Text PDF PubMed Scopus (1297) Google Scholar p53 has been extensively studied for its role in suppressing tumorigenesis and explored as a promising cancer therapeutic. Serving as a tetrameric transcriptional factor,13el-Deiry W.S. Kern S.E. Pietenpol J.A. Kinzler K.W. Vogelstein B. Definition of a consensus binding site for p53.Nat. Genet. 1992; 1: 45-49Crossref PubMed Google Scholar, 14Funk W.D. Pak D.T. Karas R.H. Wright W.E. Shay J.W. 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Understanding the non-canonical pathways involved in p53-mediated tumor suppression.Carcinogenesis. 2014; 35: 740-746Crossref PubMed Scopus (0) Google Scholar Importantly, WT p53 can exist in at least 12 isoforms, which are generated through different promoters, alternative splicing, and translation start sites.18Surget S. Khoury M.P. Bourdon J.C. Uncovering the role of p53 splice variants in human malignancy: a clinical perspective.Onco Targets Ther. 2013; 7: 57-68Crossref PubMed Scopus (68) Google Scholar Although physical and functional interactions between these isoforms are not well understood, some of the them inhibit or stimulate biological activities of WT p53.18Surget S. Khoury M.P. Bourdon J.C. Uncovering the role of p53 splice variants in human malignancy: a clinical perspective.Onco Targets Ther. 2013; 7: 57-68Crossref PubMed Scopus (68) Google Scholar Moreover, to be functional, p53 requires homotetramerization of four subunits of p53, and its activities are modified by more than 50 different posttranslational modifications, including phosphorylation, methylation, acetylation, glycosylation, ubiquitylation, sumoylation, neddylation, nitration, and poly-ribosylation.19Dai C. Gu W. p53 post-translational modification: deregulated in tumorigenesis.Trends Mol. Med. 2010; 16: 528-536Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Additionally, the p53 tumor suppressor family includes two other members, tumor protein p63 (TP63) and tumor protein p73 (TP73), which share homology with p53 at the N-terminal transactivation domain, the central core domain for DNA binding, and the C-terminal oligomerization domain.20Sasaki Y. Oshima Y. Koyama R. Tamura M. Kashima L. Idogawa M. Yamashita T. Toyota M. Imai K. Shinomura Y. Tokino T. A novel approach to cancer treatment using structural hybrids of the p53 gene family.Cancer Gene Ther. 2012; 19: 749-756Crossref PubMed Google Scholar However, unlike p53, p63 and p73 contain an additional Sterile Alpha Motif (SAM) domain, which plays a role in protein-protein interactions and in lipid binding.21Thanos C.D. Bowie J.U. p53 family members p63 and p73 are SAM domain-containing proteins.Protein Sci. 1999; 8: 1708-1710Crossref PubMed Google Scholar, 22Barrera F.N. Poveda J.A. González-Ros J.M. Neira J.L. Binding of the C-terminal sterile alpha motif (SAM) domain of human p73 to lipid membranes.J. Biol. Chem. 2003; 278: 46878-46885Crossref PubMed Scopus (0) Google Scholar Contrary to p53, the tetramerization domains of p63 and p73 proteins can lead to the formation of mixed heterotetramers consisting of p63 and p73, but not p53, subunits.23Joerger A.C. Rajagopalan S. Natan E. Veprintsev D.B. 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WT p53 is a key player in cancer development not only because of its normal functions as a powerful tumor suppressor, but also through its devastating roles once mutated, mostly via missense mutations (especially at hotspots V157, R158, R175, G245, R248, R249, and R273).30Kandoth C. McLellan M.D. Vandin F. Ye K. Niu B. Lu C. Xie M. Zhang Q. McMichael J.F. Wyczalkowski M.A. et al.Mutational landscape and significance across 12 major cancer types.Nature. 2013; 502: 333-339Crossref PubMed Scopus (926) Google Scholar Those mutations have two major consequences: First, they can cause the loss of function of normal p53 via several mechanisms. In particular, in the heterozygous form, many mutant p53 proteins show a dominant-negative effect via heterotetramerization with WT p53, preventing its normal checkpoint functions.31Chène P. The role of tetramerization in p53 function.Oncogene. 2001; 20: 2611-2617Crossref PubMed Scopus (135) Google Scholar Second, many p53 mutants acquire gain-of-function oncogenic activities, promoting cell survival, proliferation, invasion, migration, chemoresistance, tissue remodeling, chronic inflammation, as well as inactivation of p53 paralogs p63 and p73, which belong to the same p53 tumor suppressor family and are important tumor suppressors.32Muller P.A. Vousden K.H. p53 mutations in cancer.Nat. Cell Biol. 2013; 15: 2-8Crossref PubMed Scopus (465) Google Scholar, 33Mantovani F. Walerych D. Sal G.D. Targeting mutant p53 in cancer: a long road to precision therapy.FEBS J. 2017; 284: 837-850Crossref PubMed Scopus (0) Google Scholar Not surprisingly, tumors depleted of the WT p53 gene retain the mutant form of the protein and thus gain a selective advantage.34Alexandrova E.M. Yallowitz A.R. Li D. Xu S. Schulz R. Proia D.A. Lozano G. Dobbelstein M. Moll U.M. Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment.Nature. 2015; 523: 352-356Crossref PubMed Scopus (0) Google Scholar Importantly, although p53 mutations are present in approximately 50% of cancers, in almost all cases where WT p53 is retained, its tumor suppressor function is eliminated via direct binding of two main p53 binding protein groups: (1) cellular mouse double minute 2 homolog (MDM2) or transformed mouse 3T3 cell double minute 4 (MDM4: also known as MDMX),35Ashcroft M. Vousden K.H. Regulation of p53 stability.Oncogene. 1999; 18: 7637-7643Crossref PubMed Google Scholar, 36Gu J. Kawai H. Nie L. Kitao H. Wiederschain D. Jochemsen A.G. Parant J. Lozano G. Yuan Z.M. Mutual dependence of MDM2 and MDMX in their functional inactivation of p53.J. Biol. Chem. 2002; 277: 19251-19254Crossref PubMed Scopus (0) Google Scholar or (2) proteins encoded by DNA viruses such as the E6 protein of high-risk human papillomavirus (HPV).37Hengstermann A. Linares L.K. Ciechanover A. Whitaker N.J. Scheffner M. Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells.Proc. Natl. Acad. Sci. USA. 2001; 98: 1218-1223Crossref PubMed Google Scholar Finally, mutations in the conformation-sensitive core domain of p53 induce the association of p53 with chaperone proteins such as heat shock protein 90 (Hsp90) forming a complex p53-Hsp90-MDM2 and provoking the MDM2 inhibition leading to the stabilization of p53 mutants.38Peng Y. Chen L. Li C. Lu W. Chen J. Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization.J. Biol. Chem. 2001; 276: 40583-40590Crossref PubMed Scopus (0) Google Scholar Various pharmaceutical approaches have been developed to restore the WT function of p53 mutants (using p53 reactivation and induction of massive apoptosis [PRIMA-1], SH group-targeting compound that induces massive apoptosis [STIMA-1], CP-31398, and other compounds) or to block interactions of WT p53 with MDM2/MDMX (using nutlin-3a, RG7112, CGM097, SAR405838, and other compounds).28Martin A.G. Trama J. Crighton D. Ryan K.M. Fearnhead H.O. Activation of p73 and induction of Noxa by DNA damage requires NF-kappa B.Aging (Albany NY). 2009; 1: 335-349Crossref PubMed Google Scholar, 29Farhang Ghahremani M. Goossens S. Haigh J.J. The p53 family and VEGF regulation: "It's complicated".Cell Cycle. 2013; 12: 1331-1332Crossref PubMed Scopus (0) Google Scholar, 39Duffy M.J. Synnott N.C. McGowan P.M. Crown J. O'Connor D. Gallagher W.M. p53 as a target for the treatment of cancer.Cancer Treat. Rev. 2014; 40: 1153-1160Abstract Full Text Full Text PDF PubMed Google Scholar, 40Parrales A. Iwakuma T. Targeting oncogenic mutant p53 for cancer therapy.Front. Oncol. 2015; 5: 288Crossref PubMed Google Scholar Each of these approaches has its limitations. For example, it is unclear whether PRIMA-1 and similar compounds effectively target all mutant p53 variants and whether the tumor suppressor functions of p63 and p73 could be negatively affected by these drugs. Further, although MDM2/MDMX antagonists may be beneficial in cancers with WT p53 and high MDM2/MDMX expression, they are unlikely to be effective in tumors with a high prevalence of p53 mutations, where Hsp90 inhibits MDM2-mediated mutant p53 degradation.38Peng Y. Chen L. Li C. Lu W. Chen J. Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization.J. Biol. Chem. 2001; 276: 40583-40590Crossref PubMed Scopus (0) Google Scholar Moreover, because in the absence of this Hsp90 activity MDM2 is able to inactivate p53,38Peng Y. Chen L. Li C. Lu W. Chen J. Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization.J. Biol. Chem. 2001; 276: 40583-40590Crossref PubMed Scopus (0) Google Scholar, 41Stindt M.H. Muller P.A. Ludwig R.L. Kehrloesser S. Dötsch V. Vousden K.H. Functional interplay between MDM2, p63/p73 and mutant p53.Oncogene. 2015; 34: 4300-4310Crossref PubMed Scopus (14) Google Scholar, 42Muller P.A. Vousden K.H. Mutant p53 in cancer: new functions and therapeutic opportunities.Cancer Cell. 2014; 25: 304-317Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar the use of MDM2/MDMX antagonists in premalignant lesions may increase the number of p53 mutant forms and the risk of tumor progression. Indeed, long-term exposure to nutlin-3a promotes the emergence of p53 mutations.29Farhang Ghahremani M. Goossens S. Haigh J.J. The p53 family and VEGF regulation: "It's complicated".Cell Cycle. 2013; 12: 1331-1332Crossref PubMed Scopus (0) Google Scholar, 30Kandoth C. McLellan M.D. Vandin F. Ye K. Niu B. Lu C. Xie M. Zhang Q. McMichael J.F. Wyczalkowski M.A. et al.Mutational landscape and significance across 12 major cancer types.Nature. 2013; 502: 333-339Crossref PubMed Scopus (926) Google Scholar, 40Parrales A. Iwakuma T. Targeting oncogenic mutant p53 for cancer therapy.Front. Oncol. 2015; 5: 288Crossref PubMed Google Scholar, 43Michaelis M. Rothweiler F. Barth S. Cinatl J. van Rikxoort M. Löschmann N. Voges Y. Breitling R. von Deimling A. Rödel F. et al.Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells.Cell Death Dis. 2011; 2: e243Crossref PubMed Scopus (70) Google Scholar Many of these challenges associated with p53 could be more effectively addressed through the development of approaches allowing successful delivery and expression of the WT p53 transgene in tumor cells. Unlike the pharmaceutical approaches described above, p53 gene therapy is expected to be effective independently of the p53 tumor status. The history of p53 as a cancer gene therapeutic has been reviewed.44Lane D.P. Cheok C.F. Lain S. p53-based cancer therapy.Cold Spring Harb. Perspect. Biol. 2010; 2: a001222Crossref Google Scholar In brief, in the late 1980s and early 1990s it was known that treatment of cancer cells with WT p53 resulted in senescence45Xue W. Zender L. Miething C. Dickins R.A. Hernando E. Krizhanovsky V. Cordon-Cardo C. Lowe S.W. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.Nature. 2007; 445: 656-660Crossref PubMed Scopus (1135) Google Scholar or apoptosis46Ventura A. Kirsch D.G. McLaughlin M.E. Tuveson D.A. Grimm J. Lintault L. Newman J. Reczek E.E. Weissleder R. Jacks T. Restoration of p53 function leads to tumour regression in vivo.Nature. 2007; 445: 661-665Crossref PubMed Scopus (928) Google Scholar depending on the cancer tested. Dr. Jack Roth (MD Anderson Cancer Center) was the first to successfully use p53 therapy in vivo in humans using replication-deficient retroviral vector-driven expression of human p53 against non-small cell lung carcinoma.47Roth J.A. Nguyen D. Lawrence D.D. Kemp B.L. Carrasco C.H. Ferson D.Z. Hong W.K. Komaki R. Lee J.J. Nesbitt J.C. et al.Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer.Nat. Med. 1996; 2: 985-991Crossref PubMed Scopus (637) Google Scholar The focus of the p53-based cancer gene therapy field then shifted to replication-deficient adenoviral vectors because of their low risk of integration into the host genome, the ability of the vectors to inhibit growth of many malignancies in vitro, and the ability to achieve cost-effective, large-scale good manufacturing practice (GMP) production.44Lane D.P. Cheok C.F. Lain S. p53-based cancer therapy.Cold Spring Harb. Perspect. Biol. 2010; 2: a001222Crossref Google Scholar Since then, many clinical trials were conducted using different p53 expression replication-deficient viral vectors (discussed below), with thousands of patients receiving the therapies without significant adverse effects. This approach also had limited success.44Lane D.P. Cheok C.F. Lain S. p53-based cancer therapy.Cold Spring Harb. Perspect. Biol. 2010; 2: a001222Crossref Google Scholar To date, no such therapeutic approach has been approved in the United States. This review discusses the large number of preclinical studies combining the benefits of replication-competent OV therapy with p53 gene therapy in vitro and/or in vivo. First, we highlight how the expression of WT p53 transgenes improves OV therapy safety and oncoselectivity, increases oncotoxicity, and augments anti-tumor effects by promoting the stimulation of anti-cancer immune responses. We also review strategies to modify and improve p53 activities to counteract cancer cell resistance to p53 gene therapy. To facilitate comparisons, we organize OV-p53 viruses (WT or modified transgenes) (see Table 1) based on their modifications and the issues they address. Finally, we review preclinical and clinical studies (see Table 2) that utilized replication-deficient gene therapy vectors expressing a p53 transgene, with a focus on their prospective use in the context of OV therapy.Table 1OVs Encoding p53 or p53 Family MembersOV NameVirus Genome ModificationsTransgene Location in Viral GenomeTransgene ModificationsCancer TargetedToxicological StudyIn Vitro EffectsIn Vivo Tumor and Mice ModelsVirus Dose (Total) and Injection ModeIn Vivo EffectsTherapeutic CombinationReferencesAdenovirus SG600-p53E1a CR2-deleted 24 nt (nt 923–946); E1a under hTERT promoter; E1b under HRE cis-elementsTP53 between E1a and E1bWT gene under CMV promoter–yes––1–4 × 1011 VP/kg (i.v.) for safety pharmacology, 2.5 × 1013 VP/kg (i.m.) for acute toxicity test via one injection↑ safety ↑ toleration no adverse effects–57Su C. Cao H. Tan S. Huang Y. Jia X. Jiang L. Wang K. Chen Y. Long J. Liu X. et al.Toxicology profiles of a novel p53-armed replication-competent oncolytic adenovirus in rodents, felids, and nonhuman primates.Toxicol. Sci. 2008; 106: 242-250Crossref PubMed Scopus (13) Google ScholarAdenovirus SG600-p53E1a CR2-deleted 24 nt (nt 923–946); E1a under hTERT promoter; E1b under HRE cis-elementsTP53 between E1a and E1bWT gene under CMV promoterlung, liver, cervical, pancreasno↑ oncoselectivity ↑ p53 expression ↑ cytotoxicitylung subcutaneous xenograft (NCI-H1299) BALB/c nude mice5 × 108 to 2 × 109 PFU (i.t.) via five injections↓ tumor growth ↑ necrosis areas ↑ p53 level in cancer cells injected ↑ apoptosis–168Wang X. Su C. Cao H. Li K. Chen J. Jiang L. Zhang Q. Wu X. Jia X. Liu Y. et al.A novel triple-regulated oncolytic adenovirus carrying p53 gene exerts potent antitumor efficacy on common human solid cancers.Mol. Cancer Ther. 2008; 7: 1598-1603Crossref PubMed Scopus (0) Google ScholarAdenovirus SG635-p53E1a CR2-deleted 24 nt (nt 923–946); E1a under hTERT promoter; E1b under HRE cis-elements Ad35 (shaft + knob)TP53 between E1a and E1bWT gene under CMV promoterbreastno↑ infectivity ↑ viral replication ↑ p53 expression ↑ viral progeny production ↑ cytotoxicitybreast subcutaneous xenograft (Bcap-37) BALB/c nude mice1 × 109 PFU (i.t.) via five injections↑ cell growth inhibition ↑ necrosis area ↑ viral progeny production ↑ p53 level in cancer cells injected–169He X. Liu J. Yang C. Su C. Zhou C. Zhang Q. Li L. Wu H. Liu X. Wu M. Qian Q. 5/35 fiber-modified conditionally replicative adenovirus armed with p53 shows increased tumor-suppressing capacity to breast cancer cells.Hum. Gene Ther. 2011; 22: 283-292Crossref PubMed Scopus (0) Google ScholarAdenovirus AdSurp-p53E1a under Survivin promoterTP53 upstream E1aWT gene under CMV promotergallbladder, hepaticno↑ cytotoxicity ↑ oncoselectivity ↑ p53 level ↑ viral proliferationgallbladder subcutaneous xenograft (EH-GB1) BALB/c nude mice1 × 109 PFU (i.t.) via five injections↑ tumor growth inhibition ↑ p53 expression in cancer cells ↑ apoptosis ↑ necrosis area–170Liu C. Sun B. An N. Tan W. Cao L. Luo X. Yu Y. Feng F. Li B. Wu M. et al.Inhibitory effect of Survivin promoter-regulated oncolytic adenovirus carrying P53 gene against gallbladder cancer.Mol. Oncol. 2011; 5: 545-554Crossref PubMed Scopus (0) Google ScholarAdenovirus AdCB016-mp53(268N)E1a CR1-deleted (aa 27–80); E1a CR2-deleted 24 nt (aa 122–129)TP53 in E3mutation (D268N)cervicalno↑ oncoselectivity ↑ cytotoxicity ↑ resistance to HPV E6 ↑ p53 transactivation function in E6-positive cellsNDNDND–94Heideman D.A. Steenbergen R.D. van der Torre J. Scheffner M. Alemany R. Gerritsen W.R. Meijer C.J. Snijders P.J. van Beusechem V.W. Oncolytic adenovirus expressing a p53 variant resistant to degradation by HPV E6 protein exhibits potent and selective replication in cervical cancer.Mol. Ther. 2005; 12: 1083-1090Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarAdenovirus OV.shHDAC1.p73E1a CR2-deleted 24 nt (nt 923–946); shHDAC1 between E4 and right terminal repeatTP73 in fiberWT genemelanomano↑ cytotoxicity lifting of epigenetic blockage ↑ apoptosis ↑ autophagy no inhibition of viral replication ↑ viral progeny productionsubcutaneous xenograft (SK-Mel-147) NMRI nude mice3 × 108 PFU (i.t.) via three injections↓ tumor growth no recurrence ↑ survivalshRNA against HDAC1127Schipper H. Alla V. Meier C. Nettelbeck D.M. Herchenröder O. Pützer B.M. Eradication of metastatic melanoma through cooperative expression of RNA-based HDAC1 inhibitor and p73 by oncolytic adenovirus.Oncotarget. 2014; 5: 5893-5907Crossref PubMed Google ScholarAdenovirus Adp53rcADP deletionTP53 in fiber; E3 deletionWT genelungnono inhibition of viral replication ↑ viral spread ↑ p53 level exogenous p53 in the nucleus ↑ oncolytic activity ↑ apoptosis––––171Sauthoff H. Pipiya T. Heitner S. Chen S. Norman R.G. Rom W.N. Hay J.G. Late expression of p53 from a replicating adenovirus improves tumor cell killing and is more tumor cell specific than expression of the adenoviral death protein.Hum. Gene Ther. 2002; 13: 1859-1871Crossref PubMed Scopus (49) Google ScholarAdenovirus Adp53W23SADP deletion; E3 deletionTP53 in fibermutation (W23S)lung, colorectalnono inhibition of viral replication ↑ viral spread ↑ resistance to E1b-55kD and MDM2 nuclear localization of p53 no export to cytosol ↑ p53 level ↑ p53 half-life (stability) ↑ cytotoxicity mildly decreased p53 transactivationsubcutaneous xenograft (A549) NCrNU-M nude mice1 × 109 PFU (i.t.) via one injectionTumor size unaffected by p53 expression ↑ p53 expression in cancer cells from virus-infected areas p53 nuclear expression–83Sauthoff H. Pipiya T. Chen S. Heitner S. Cheng J. Huang Y.Q. Rom W.N. Hay J.G. Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53.Cancer Gene Ther. 2006; 13: 686-695Crossref PubMed Scopus (8) Google ScholarAdenovirus AdΔ24-p53E1a CR2-deleted 24 nt (aa 122–129)TP53 in E3WT genediverse human cancer cellsno↑ cytotoxicity ↑ early virus release oncolysis independent of E1a binding to pRb and independent of E3 functions––––74van Beusechem V.W. van den Doel P.B. Grill J. Pinedo H.M. Gerritsen W.R. Conditionally replicative adenovirus expressing p53 exhibits enhanced oncolytic potency.Cancer Res. 2002; 62: 6165-6171PubMed Google ScholarAdenovirus AdΔ24-p53E1a CR2-deleted 24 nt (aa 122–129)TP53 in E3WT geneneuroblastomano↑ cytotoxicity effect independent of endogenous p53 cellular statussubcutaneous xenografts (IGR-N91, IGR-NB8) SPF-Swiss athymic nude mice5 × 108 PFU (i.t.) via five injections↓ tumor growth ↑ cell lysis ↑ apoptosis ↑ fibrous fascicles ↑ necrosis areas–76Geoerger B. van Beuseche
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